Edible holographic products, particularly pharmaceuticals and methods and apparatus for producing same

ABSTRACT

An edible product such as a unit dosage form of a pharmaceutically active substance includes a layer of a material that can receive and retain a high resolution microrelief that can convey information. The microrelief is themo-formable, preferably formed from an aqueous solution of HPMC and/or HPC plus a plasticizer and colorant. Other additives such as strengtheners, surfactants and adherents may be used depending on the application. The materials are selected and proportioned to control the fading or change in color of the visual image or effect produced by the relief to indicate exposure to an unacceptable degree of heat or humidity. The dosage form can be the relief-containing layer itself with the pharmaceutical carried therein. In a preferred form, the layer is an outer coating over a core containing the pharmaceutically active substance. Coated tablets are configured to resist twinning. To produce such dosage forms, the coated core is transported in unison with a flexible mold or transfer plate that can heat-replicate the microrelief on the outer layer of the dosage form, followed by a cooling and release of the transfer plate from the coating.

FIELD OF THE INVENTION

This invention relates in general to solid dosage forms bearingdiffraction reliefs capable of conveying information, such as thereconstruction of holographic images, as well as methods and apparatusfor producing same.

BACKGROUND OF THE INVENTION

The creation of holographic images using fine diffraction patternsilluminated with laser light is well known. White-light “holograms” arealso well known. A common example of Benton white-light “holograms” isthe creation of images on credit cards and the like to prevent tamperingwith information carried on the cards, and to enhance their visualaesthetics. Known images include rainbow-like color patterns, pictures,and changes in color or location of pictures or parts of pictures with achange in viewing angle.

While it is also known to emboss a suitable relief on a section of agenerally flat sheet of plastic material, such as that forming a creditcard, with a heated metal die, the production of high resolutiondiffraction reliefs on edible products presents special problems.Materials suitable for receiving and retaining diffraction reliefs onedible products must not only be capable of receiving a fine pattern,e.g., 1,000 to 5,000 lines per mm, and be capable of retaining that finepattern (be stable), but they must also be food safe and palatable.Retention requires resistance to mechanical degradation during routinehandling as well as the adverse effects of water, especially air-bornehumidity and heat. Ingestibles should also be digestible, whichtypically means they should be water-soluble. (Pharmaceutical deliverysystems are known which rely on stomach acid to dissolve a coating, orwhich have a substantially indigestible coating with small holes throughwhich a pharmaceutically active substance is released.)

U.S. Pat. No. 4,668,523 to Begleiter discloses the first system forapplying a high resolution diffraction gratings to a food product toproduce edible holograms.

While such diffraction reliefs produced by dehydration in molds haveproven to be able to provide color and other visual effects on candiesand other food products, they have not heretofore been used commerciallyon dosage forms such as pharmaceuticals. Indeed, the commercialproduction of small, holographic-bearing dosage forms introducesproblems, enumerated below, not encountered using the known generalmethods for creating holographic foods such as lollipops.

Pharmaceutical products are typically sold and used in a variety offorms, each providing a known unit dosage of a pharmaceutically activeingredient. Typical forms include common compressed powder tablets andcoated tablets. The term also includes hard shell capsules and soft-gelcapsules. For the purposes of this application, these and other unitdosage delivery forms are termed “dosage forms”. These dosage formstypically include a core which, in turn, include a pharmaceuticallyactive ingredient and a pharmaceutically acceptable inert carrier. Inmany instances, the dosage form also includes an outer layer thatencloses the core, protects it, contains it (e.g., a capsule holding agranular, powdery, or viscous core material), and/or provides a vehiclefor carrying a material that facilitates use of the dosage form, e.g., a“buffered” coating on an aspirin tablet.

In the pharmaceutical field, it is important to identify anddifferentiate one product from another reliably. The consumer needs tobe sure of what medicine he/she is taking. The manufacturer isinterested in establishing brand identity and extending brand loyalty.It is also of interest to be able to deter counterfeits and to covertlydifferentiate dosage forms, e.g., for use in double blind tests.

Pharmaceuticals and food products have been limited to the use ofcertain FDA and other internationally approved colors producedchemically by dyes and lakes. Many countries have different regulationsgoverning the use of these chemicals leading to difficulty in creatinguniform product identities for pharmaceutical companies acrossinternational borders. Further, it would be desirable to have thecapability of producing a greater variety of colors beyond the few thathave regulatory approval—especially “rainbow-like” effects produced bythe juxtaposition of multiple colors of gradually varying wavelength.

Monitoring of storage conditions is important in preserving productintegrity.

“Edible Holography: The application of holographic techniques to foodprocessing”, SPIE, Vol. 1461, “Practical Holography V” (1991) at pages102-109 discusses the use of a punch die to compress a powder into atablet while simultaneously using a metal die plate to impress amicrorelief as the powder becomes a solid core in a tablet press. Rapiddie wear and difficulty in releasing the compressed core from the dieare just some of the problems that limit this technique.

More generally, a commercially viable system for holographicallyconveying information on pharmaceuticals must address a variety ofrequirements beyond those discussed above for food products. A majordifference is that pharmaceutical dosage forms are “non-deposited”, thatis, they are not poured into a mold as a liquid to be formed, as withhard candy. Also pharmaceutical dosage forms are small as compared topresent commercial edible products such as lollipops, and they can havenon-planar outer surfaces where it would be desirable to carry aholographic diffraction pattern. In addition, the material in which themicrorelief is formed cannot interact adversely with thepharmaceutically active ingredient(s) to reduce its efficacy, and shouldnot otherwise be objectionable when ingested, e.g., allergenic. Theimage-producing microrelief on a dosage form must also be reliablydurable and stable during manufacture, packaging, shipment, and underacceptable storage conditions, that is, conditions that do not adverselyaffect the efficacy or required product life of the dosage form. Themicrorelief should have a long shelf life, which requires a highresistance to changes in shape on the micron scale due to appliedmechanical stresses, and degradation due to temperature changes or tothe absorption of moisture. Such a microrelief is termed “stable”. Ifapplied as a layer on a core, the layer containing the relief should notdelaminate or “bubble”. Bubbling is a particular concern when heat isused in applying or processing the layer.

Suitable microreliefs used on pharmaceuticals should be compatible withmodern dosage form manufacturing equipment and techniques and beeconomical in its implementation. A microrelief must also benon-detrimental to the efficacy of the pharmaceutical. Any heat used aspart of the manufacturing process for implementing a microrelief shouldnot degrade the efficacy of pharmaceutically active ingredient(s). Whileholograms transfer and reconstruct best on flat surfaces, coated tabletswith flat faces tend to adhere to one another, or “twin”, during thecoating process. The production of diffraction microreliefs on coatedproducts should resist twinning in order to maintain acceptable yieldratios. Suitable microreliefs should also be formed using materials thatdo not require new regulatory approval.

It is also desirable to know if an ingestible product is likely to haveretained its efficacy after it has been manufactured and stored. Statedin other words, it would be useful to have a readily visible indicatorof the environmental history of any given dosage form. Such anindicator, for example, would usefully indicate whether a dosage formhad been exposed to high temperatures, e.g., over 100° F., and highhumidities, e.g., over 80% relative humidity (RH), for any extendedperiod of time during storage or prior to sale or use. This problem iscommonly addressed by printing an expiration date on a container for theproduct. However, it would be better if there was some visual indicationof efficacy on the product itself.

It is therefore a principal object of this invention to provide anedible product, including a dosage form in any of a wide variety ofshapes and configurations, that has a stable microrelief whose stabilitycan be controlled, and that conveys information such as visualholographic images and effects.

Another principal object is to provide specific, approved materials,methods and apparatus for producing such a product that are costeffective and compatible with modern high-speed production equipment andtechniques such as tablet coating apparatuses.

Yet another object of this invention is to provide a system forintroducing holographic brand identification for a wide range of edibleproducts in a wide range of forms.

Another object is to provide a visual quality control indication on eachdosage form in the form of a hologram that visibly changes if the dosageform has been exposed to severe adverse conditions of temperature orhumidity.

A further object is to provide a system for controlling and detectingcounterfeit dosage forms.

Still another object is to provide dosage forms with covert identifierssuitable for use in double blind studies.

Another object is to provide the foregoing advantages without requiringa new regulatory approval of the dosage form.

Yet another object is to provide color and visual images and effects forfood products and for pharmaceuticals, (1) without the use of FDAregulated colors, dyes, inks, or metals, or (2) with colors other thanthose which are FDA approved, or (3) with the use of FDA approvedcolorant only as a contrast color to make holographic effects and imagesmore readily visible.

SUMMARY OF THE INVENTION

Broadly stated, the invention provides pharmaceutical dosage forms andother edibles products bearing a microrelief, and in particular a highresolution diffraction relief. The diffraction relief is thermoformed ina layer of a suitable material, and once formed, is stable. Theinvention further provides the materials, apparatus and processeswhereby such diffraction reliefs can be applied. By means of thisinvention, a microrelief capable of diffracting light may be applieddirectly to a product such as a dosage form.

The present invention allows monitoring of storage conditions topreserve product integrity. Edible diffractive gratings as a structuralcomponent of a dosage form have the ability to make visible to theunaided eye microscopic changes, caused by heat and moisture, which canalter the depth and spacing of the grating and so change the ways inwhich it interacts with light. Thus over-all coating changes such asexpansion even as small as the wavelength of light can be detected bythe unaided eye through changes in color reconstruction angles anddiffraction efficiency.

The invention provides the economical production of edible colorswithout the necessity of adding to the product objectionable materialssuch as certain dyes, inks, aluminum lakes, metals such as gold orsilver or minerals such as mica.

In one embodiment of this aspect, the invention provides a dosage formcomprising:

a core which comprises a pharmaceutically active substance and apharmaceutically acceptable carrier;

athermoformable solid outer layer overlaying said core, and amicrorelief in said layer.

The layer of material that retains the microrelief in one form is pancoated onto the core and completely encloses it. In another form thislayer partially covers the core. It can be printed or laminated onto thecore. In still another form, the layer itself can contain apharmaceutically active material and constitute the entire dosage form.

This layer is formed from an aqueous solution of a thermoformablematerial selected from the group consisting of modified cellulose,modified food starch, gelatin, waxes, vegetable gums, and combinationsthereof. The preferred material comprises a modified cellulose, namely,hydroxyproplymethlcellulose (HPMC), hydroxypropylcellulose (HPC), andmixtures thereof.

The material also preferably includes a plasticizer and a colorant. Thechoice of plasticizer and/or thermoformable material and the relativeportions are adjusted to control the response of the microrelief overtime to humidity. Oils and waxes with varying melting points admixed tothis layer provide control over the response of the microrelief overtime to temperature. Fading or change of color (due to a change in thereconstruction angle) of the visual image or effect produced by themicrorelief provides a visual indication of the environmental history ofthe dosage form and its integrity. Suitable waxes include paraffin (alow melting point) and carnuba (a high melting point). Suitablehygroscopic plasticizers include sugars such as dextrose (highlyhygroscopic) and proplyeneglycol.

When the dosage forms are made by pan coating, the cores are configuredto resist twinning by reducing the amount of the flat area at theoutermost surface of the dosage form and by convexly curving theoutermost surfaces, particularly the faces of tablets. Flat areareduction includes forming a recess in each face of a tablet with agenerally flat bottom that receives and retains the microrelief.

Broadly stated, a method of producing a microrelief on a dosage formaccording to the present invention includes the steps of:

-   -   a. coating the core with a layer of a thermoformable material        that can receive and retain a holographic diffraction pattern;    -   b. providing a plate having a holographic diffraction pattern        formed on at least a portion of a first surface thereof;    -   c. transporting said coated cores to a position opposite that        first plate surface;    -   d. heating at least one of the plate and the coated layer during        or prior to the time when they are in said opposed relationship;    -   e. pressing the first plate surface into the coated layer to        replicate the holographic diffraction pattern in the coated        layer;    -   f. cooling the coated layer thus replicated; and    -   g. demolding the first plate surface from the coated layer.

Broadly stated, apparatus for the continuous (non-batch) production of amircorelief on a core which can contain a pharmaceutically activesubstance and which is coated with a thin layer of a thermo-formable,includes

-   -   -   a conveyor that carriers the coated cores in a first            direction,

    -   a plate containing a holographic diffraction pattern on one        surface thereof facing the coated cores on the conveyor, the        plate being movable along the first direction in coordination        with the carrying, and with the one plate surface spaced from        the coated cores,

    -   a heater for rapidly raising the temperature of one of the plate        and the thin layer of coating to a level where the coating layer        is formable,

    -   apparatus for pressing the one plate surface into the coating        layer after the heating to replicate the diffraction pattern in        the coating layer,

    -   a cooler to rapidly lower the temperature of the coating layer        to stabilize the diffraction pattern in the coating layer, and

    -   apparatus to separate the one plate surface from the coating        layer.

These and other features and objects will be readily understood from thefollowing detailed description of the preferred embodiments that shouldbe read in light of the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view in end elevation of a coated, curved-face tabletaccording to the present invention;

FIG. 2 is a top plan view of an alternative coated, curved-face tabletaccording to the present invention with lettering on one face;

FIG. 2A is a view in end elevation of the tablet shown in FIG. 2;

FIG. 2B is a view in side elevation of the tablet shown in FIGS. 2 and2B;

FIG. 2C is a detailed view in vertical section of the lettering takenalong the line 2C-2C in FIG. 2;

FIG. 3 is a top plan view corresponding to FIG. 2 of an alternativeembodiment according to the present invention with flat faces and slopededges;

FIG. 3A is a view in end elevation of the coated tablet of FIG. 3;

FIG. 3B is a view in side elevation of the tablet shown in FIG. 3;

FIG. 3C is a detailed view in vertical section of the lettering takenalong the line 3C-3C in FIG. 3;

FIG. 4 is a top plan view corresponding to FIG. 3 of another coatedtablet according to the present invention with flat central faces androunded edges;

FIG. 4A is a view in end elevation of the tablet shown in FIG. 4;

FIG. 4B is a view in side elevation of the tablet shown in FIG. 4;

FIG. 4C is a detailed view in vertical section taken along the line4C-4C in FIG. 4;

FIG. 5 is a top plan view of a flat-faced, coated tablet according tothe present invention with a central recess and rounded edges;

FIG. 5A is a view in end elevation of the tablet shown in FIG. 5;

FIG. 5B is a view in side elevation of the tablet shown in FIG. 5;

FIG. 5C is a detailed view in vertical section taken along the line5C-5C in FIG. 5;

FIG. 6 is a top plan view of an alternative embodiment of a flat-faced,coated table with a double recess according to the present invention;

FIG. 6A is a view in end elevation of the tablet shown in FIG. 6;

FIG. 6B is a view in side elevation of the tablet shown in FIG. 6;

FIG. 6C is a view in vertical section taken along the line 6C-6C in FIG.6;

FIG. 7 is a view in side elevation of a tablet according to the presentinvention with a section of a layer containing a microrelief pattern,and adhered to a tablet core;

FIG. 8 is a perspective view of a capsule according to the presentinvention with a portion broken away to show a loose or viscous corematerial contained therein and where the capsule itself has amicrorelief pattern formed therein;

FIG. 9 is a perspective view of a soft gel capsule according to thepresent invention with a portion broken away to show a viscous corematerial contained therein and where the capsule itself has amicrorelief pattern formed therein;

FIG. 10 is a view in side elevation of a holographic dosage formaccording to the present invention where a layer carrying a microreliefpattern itself has a pharmaceutically active ingredient(s) therein;

FIG. 11 is a perspective view of a package of plural dosage forms;

FIGS. 12A-H each show alternative arrangements in both top plan and sideelevational views, except FIG. 12C which is in plan view only, accordingto the present invention for controlling twinning of coated tablets;

FIG. 13 is a simplified view in perspective of a belt-type apparatusaccording to the present invention with a moving transfer plate formanufacturing holographic pharmaceuticals also according to the presentinvention;

FIG. 14 is a view in side elevation of the apparatus shown in FIG. 13;

FIG. 15 is a detailed view in perspective of the moving transfer platethermoforming assembly shown in FIGS. 13 and 14;

FIG. 16 is a simplified perspective view of a belt-type, twin movingtransfer plate apparatus according to the present invention formanufacturing holographic pharmaceuticals also according to the presentinvention;

FIG. 17 is a view in side elevation of the apparatus shown in FIG. 16;

FIG. 18 is a simplified perspective view of an alternative embodiment ofa belt-type, twin moving transfer plate apparatus according to thepresent invention for manufacturing holographic pharmaceuticals;

FIG. 19 is a view in side elevation of the apparatus shown in FIG. 18;

FIG. 20 is a top plan view of a slat-segment conveyor belt according tothe present invention;

FIG. 20A is a view in section taken along the line 20A-20A in FIG. 20;

FIG. 21 is a simplified view in perspective of a linearframe-and-transfer plate type of apparatus for manufacturing holographicpharmaceuticals according to the present invention;

FIG. 22 is a detailed view in perspective of theframe-and-transfer-plate unit shown in FIG. 21;

FIG. 23 is a top plan view of an apparatus using the constructions and amethod of operation according to FIGS. 20 and 21;

FIGS. 24A and 24B are views in side elevation of the apparatus shown inFIG. 23 taken along the lines 24A-24A and 24B-24B, respectively;

FIG. 25 is a view in perspective of an alternative embodiment of arotary apparatus according to the present invention operating onframe-and-transfer-plate units of the type shown in FIG. 22;

FIG. 26 is a view in perspective of an alternative rotaryframe-and-transfer-plate-type apparatus according to the presentinvention;

FIG. 27 is a view in side elevation of the apparatus shown in FIG. 27;

FIG. 28 is a detailed view in perspective of the replication assemblyshown in FIGS. 26 and 27;

FIG. 29 is a view in perspective of a rotary die punch apparatusaccording to the present invention;

FIG. 30 is a detailed view in perspective of several die punches shownin FIG. 29 with a pivoted central tab operable to eject a tablet;

FIG. 31 is a flow diagram showing a highly generalized process accordingto the present invention for thermal forming a microrelief pattern on asolid, coated dosage form;

FIG. 32 is a schematic view in perspective of an apparatus according tothe present invention for direct laser imprinting a diffraction reliefpattern in an outer coating layer of a dosage form; and

FIG. 33 is a view in perspective of an alternative apparatus accordingto the present invention that operates in the style of a high speedprinter.

DETAILED DESCRIPTION OF THE REFERRED EMBODIMENTS

While the present invention can be used to create reliefs in a varietyof ingestible dosage forms, including confections, it is describedprimarily with respect to use on pharmaceutical products.

As used herein, “microrelief” means a regular pattern of grooves andridges or the like that displays optical information or a visual effect,when exposed to suitable radiant energy. “Diffraction relief” or“grating” and “microrelief” include both (1) patterns of the grooves andridges produced through laser light interference, with ruling engines,and with other known techniques which can be subsequently transferred tothe dosage form by a mold or radiant energy and (2) visual information,images and effects produced by these patterns of grooves and ridges whenproperly illuminated. A true hologram records the interference patternproduced from a laser (coherent) light source with its output beamsplit, and the image or effect is its laser light reconstruction. Asused herein, “hologram” and “holographic” are intended to include theproduction of optical information, images and effects on the dosage formas well as their reconstruction, using either laser light or white,incoherent light.

In a preferred embodiment, the diffraction relief is a high resolutiondiffraction relief. “High resolution” refers to a diffraction reliefthat is capable of diffracting visible light and having at least 400,and typically 1,000 to 5,000, lines per mm (a ½ to 1 micron phasedisplacement of grating). The dimensions of the diffraction relief areproportional to the wavelength of the light it is to interact with. TheInformation recorded and conveyed by the microrelief can be color,depth, image, optical data, and or a kinetic effect.

FIGS. 1-12 show various unit dosage forms 10 for the delivery ofpharmaceuticals by oral ingestion. “Pharmaceutically active substance”refers to ethical pharmaceuticals as well as other orally administered,ingested products such as over-the-counter medicines. Thus, the term isused in its conventional sense to mean a pharmaceutically activecompound or mixture of compounds for the treatment of a disease orcondition. The term can also refer to nutritional and diet supplementswhich are in the form of a solid dosage form. Dosage forms utilized inthe invention include all of the currently known forms such ascompressed powder tablets, coated tablets (caplets), hard and softgelatin capsules, as well as new forms such as injection-molded starchtablets, and thin-layer “sections” as shown in FIG. 10. For the purposeof this invention the dosage forms 10 which are useful within its scopewill sometimes be referred to collectively simply as “dosage forms”. Itis understood that the dosage form core can be created with or withoutpharmaceutically active compounds (such as in placebos, double blindtests and confections). “Pharmaceutical dosage form” refers to a dosageform that includes a pharmaceutically active ingredient. These forms areincluded within the scope of the invention and can be manufactured withthe disclosed methods and apparatuses. In the pharmaceutically activetablet, hard or soft gelatin capsule, and injection molded starch tabletforms, the pharmaceutically active ingredient or ingredients aretypically mixed with a carrier comprising excipients that do not reactwith the active ingredient. A core can contain conventionalpharmaceutical excipients associated with making solid dosage forms ofthe type previously mentioned, as well as others known to the art. Thussuch excipients may, depending on the exact formula, include one or morebinders, flavorings, buffers, diluents, colors, lubricants, sweeteningagents, thickening agents, and glidants. Some excipients can servemultiple functions, for example as both a binder and disintegrant.Carriers and excipients are well documented in the art. See, for exampleRemington's Pharmaceutical Sciences, Eighteenth Edition, Mack PublishingCompany, 1990, which is herein incorporated by reference.

The present invention creates dosage forms bearing diffraction reliefsthat can convey information, visible and/or covert, to the human eye innormal (e.g., daylight and/or incandescent) and/or special (e.g., laser)illumination. In at least the preferred forms, these reliefs are formedby thermal-forming in ways compatible with current high-volume,high-speed dosage form production apparatus and methods.

One aspect of the present invention is the use of an outer layer 12 of amaterial that can receive a high resolution diffraction relief 16, andretain that relief pattern reliably for the intended life of theproduct, under anticipated conditions of manufacture, handling, storageand use. In particular, it has been found that certain materials can be:(1) formed into solid outer layers or coatings around a core, (2)subsequently heated to soften (including liquefy) the layers, (3) moldedto form a high resolution diffraction relief, and then (4) cooled toretain that relief pattern in a solid form when (5) released orde-molded. General characteristics of these materials are that they havea controllable water-stability, are heat-formable, and are capable ofbeing applied to the dosage form by known pan coating, printing, orlaminating techniques. Such materials advantageously also producecoatings that are resistant to cracking, wrinkling, and/orcrystallizing, can be made to flow or bond at a temperature lower thenthat which will adversely effect the core, can retain a grating with aphase displacement on the scale of the wave length of light, arepalatable, will not interfere with the release of the cores contents,and have controllable heat and water stability in storage so as toaccurately control the fading or color. This controllable changes seenas a fading or color provides a readily visible indication of theenvironmental history of the dosage form, and its quality.

Reference to a thermoformable “layer” 10 shall be understood to includeplural thermoformable layers coated and/or deposited adjacent to eachother, for example a thermoformable base coat which is colored toprovide a background overlayed by a clear thermoformable layer whichreceives a microrelief.

More specifically, food grade materials which can function to somedegree, albeit with varying degrees of stablilty, as a thermoformableouter coating to receive and retain diffraction relief include: foodgrade sugars (i.e., glucose, fructose, sucrose, dextrose, maltose andmixtures thereof); proteins and/or polypeptides such as albumin, casein,fibrin, and collagen and gelatins, particularly Bloom strength 150 to250 gelatins; lipids such as oils, triglycerides, and fats; controllablemelting point waxes such as paraffin, carnuba, and bees; and variouspolysaccharides, namely, carbohydrates such as cellulose and starches,complex gels, modified cellulose, and hydrocolloids. Suitable modifiedcelluloses, which are presently preferred, includehydroxypropylcellulose (HPC) and hydroxypropylmethycellulose (HPMC).

For the dosage form 10 of the present invention, the diffractive reliefcontaining layer 12 is preferably formed in two coats of (1) a colorcoating or layer of an aqueous solution of the modified cellulose HPCand/or HPMC, a plasticizer, and a contrast colorant to make the hologrammore readily visible (2) a second clear coat of HPMC that overlies andcovers the color coat. If no colorant is used, either in the core or thethermoformable layer 12, a microrelief carried in the layer 12 may notbe readily visible. It can function in the nature of a watermark inquality papers. Such holograms, using no colorant in the core and aclear layer 12, can function to control counterfeits and provide theadvantages of covert information.

For the holographic pharmaceutical 10 of the present invention,adherents such as a water-based shellac, and gum starches such as gumacacia, are used in some formulations, particularly where it is desiredto adhere the layer 12 to a core 14 or to adhere a label of the layer 12to a core or to an outer coating on a dosage form.

The following Table I are examples of materials which have been mixed inan aqueous solution and tried as high resolution relief-containinglayers for the pharmaceuticals dosage forms 10: TABLE I Other ModifiedConstituent Cellulose Plasticizer Colorant Ingredient 1. HPMC P5/6Maltodextrin DE 40 2. HPMC P5/6 HPC LF 3. HPMC 606 4. HPMC E-15 Shellac(adherent) 5. HPMC Triacetin Spectraspray ™ Purple (0-340) 6. HPMCmonodiglyceride (surfactant) Shellac (adherent) 7. HPMC 606,Spectraspray Peg 400, 14.8 g 100 g red D360a, 8 g (surfactant) Water,51.8 g 8. HPMC 606, Spectraspray Peg 400, 2 g 100 g 1072, 8 g(surfactant) Water, 16 g 9. HPMC 600, Triacetin, 2 g Spectraspray Water,14 g 100 g 1072, 8 g 10. HPMC 606, Myracet, 2 g Spectraspray Marcoat ™125 50 g monodiglyceride 1072, 8 g Shellac, 20 g (surfactant) Aspartame0.015 g (sweetener) a. Undercoat Titanium dioxide 11. HPMC TriacetinDF&C blue #2, Lactose Lactose aluminum lake (flavoring) b. Overcoat HPMC12. HPMC Polyethyleneglycol Titanium dioxide 2910 3350 a. UndercoatPolyethyleneglycol Titanium dioxide 13. HPMC e-5 3350 FD&C blue #2, b.Overcoat Polyethyleneglycol aluminum lake PHMC e-5 3350 14. Gelating,Yes Corn syrup 250 Bloom (strengthener) strength glycerinThe HPMC grades (e.g., “P5/6”) above those of its manufacturer, DowChemical Co. “Spectraspray” is a trade description of a liquid colorantof Warner-Jenkines, Inc. “Marcoat” is a trade description of an aqueousshellac solution of Emerson, Inc. “DE 40” means “dextrose equivalency of40%”.

Examples Nos. 11 and 13 use two complete coatings; both can be appliedusing conventional rotating drum “pan” coaters on tablets. The undercoatpreferably carries colorant; the overcoat is clear and shiny as well ashighly stable on holding and maintaining a microrelief pattern.Strengtheners such as shellac, low conversion glucose syrup, and othersuch high molecular weight, highly cross-linked materials can be addedto toughen the layer, both to retain the pattern during release from athermal-forming die, and afterwards in handling, storage, and use. Ingeneral, long chain, high molecular weight, highly cross-linkedmaterials add strength and stability to the microrelief carrying layer12. Surfactants reduce the surface tension of the layer 12; they control“beading”.

Colorants produce a desired background or contrast color for the dosageform and the holographic image or effect produced by the microrelief.Colorants can make the relief more readily observable.

Because the layer 12 is ingested and is taken by the mouth, the layer 12can also include sweeteners to facilitate sucking and/or swallowing thedosage form or food product.

EXAMPLE 1

This example illustrates practicing a preferred embodiment usingstandard materials and coating equipment.

A first solution for applying a first (color) layer using a standard,side-vented rotating pan coater (available under the registeredtrademark ACCELACOTA from Thomas Engineering, Chicago, Ill.) was made bymixing the following components: Component Amount, wgt % aqueoussolution containing 10% 78% by weight HPMC triacetin (plasticizer) 1.6% Black FD&C color, FD&C Blue 2 6.4%  Lake, Red 40 Lake, FD&C Yellow 6Lake Water 14%The final coating solution contained approximately 12% solids by weight.

2 kg of compressed powder tablet cores of the type shown in FIG. 3 (anarc diamond shape, 0.4020 inch wide by 0.5540 inch long and about 0.243inch thick at its center) and described further below were coated in theaforementioned ACCELACOTA rotating pan cooling machine with a 15 inchrotating pan and operated under the operating conditions shown in Table1, wherein the conditions designated in the Table are those commonlyunderstood in the art. TABLE 1 Atm. Time Inlet Exhaust Air Spray MinuteWt./ml Temp C. Temp C. RPM CFM PSI g/min 0 0 70 52.5 12 240 45.9 0 5 8970 51 12 240 45.9 17.8 10 185 70 50.5 13 240 46.2 19.2 15 280 70 50.9 14240 45.7 19 20 381 69 51 15 240 45.5 20.2 25 481 68 50.5 15 240 45.6 2030 640 70 50.2 15 240 45.8 17.7

In Examples 1 and 2 “Wt/ml” is the accumulated weight increase duringthe pancoating process in the dosage forms being coated, “ml” or“milliliter” being an approximate weight measure in grams given that oneml of water weighs one gram. Inlet and outlet Temp C are the air inletand outlet temperatures to and from the coater in dgrees Centigrade.“CFM” is cubic feet per minute of this air flow through the coater and“Atm Air PSI” is the air pressure in coater in pounds per square inch.“RPM” is revolutions per minutes, the speed at which the drum of thecoater rotates. “Spray g/min” is the rate in grams per minute that theaqueous solution of the material being coated is sprayed into the drumof the coater. “Time minute” is the elapsed during operation of thepancoating for that coating. +

After applying the first coat, a second (clear) layer was applied from asolution containing the following components, the coat being appliedunder the pan coater operating conditions shown in Table 2: ComponentAmount, wgt % aqueous solution containing 10% by wgt 45% of HPMCtriacetin 0.5%  water 54.5%  

The final solution contained about 5% solids by weight. TABLE 2 Atom.Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C. RPM CFM PSIg/min 4 53 68 50.2 15 240 45.8 13.3 8.5 117 68 51 16 240 45.9 15.5

The final weight for color layer was 3%, based on the weight of thefinal tablet (i.e., the core coated with both layers). The final weightgain for clear layer was 0.25%, based on the weight of the final tablet.

A microrelief was thermally transferred to the tablets using anapparatus 69 and transfer plate 76 as shown and described in FIGS. 21-24at the preferred values given in the specification, the thermoformedmicrorelief being applied for about 2 seconds at a pressure of about 10Kg/tablet and at a temperature of about 125° C.

The coated tablets were stored for 3 weeks at 85° F. and 65% relativehumidity (RH). After the three week period, the tablets still retainedan 80-90% detraction efficiency. Tablets stored at similar temperatures,but at 80% RH, reached the point at which the microrelief started tofade, i.e., the point at which changes in the image on effect itproduced became visible and/or detectable.

EXAMPLE 2

As described in Example 1, a first color layer was formed on tablets ofthe type described in Example 1 by pan coating a solution containing thefollowing components: Component Amount, wgt % aqueous solutioncontaining 10%  68% by weight HPMC triacetin 0.5% FDA color (Blue 2aluminum   5% lake) lactose   1% titanium dioxide 0.6% water 24.9% The final solution contained approximately 12% by weight of solids.

2.2 kg of compressed tablets of the type shown in FIG. 1 (an arcuatediamond shaped, 0.4020 inch wide by 0.5540 inch long and approximately0.198 inch thick at its highest point) and described further below werecoated in the same 15 inch pan coater as described in Example 1,operated as shown in Table 3. TABLE 3 Atom. Time Inlet Exhaust Air SprayMinute Wt./ml Temp C. Temp C. RPM CFM PSI g/min 0 0 70 53.2 11 240 44.30 5 102 70 50.7 11 240 44.3 20.4 10 201 70 50.8 12 240 44.5 19.8 17 33569 50.7 12 240 44.8 20 25 494 69 51 13 240 43.1 19.5 33 650 68 52 13 24044.5 19.8

After applying the first coat, a second (clear) layer was applied from asolution containing the following components, the coat being appliedunder the pan coater operating conditions shown in Table 4: ComponentAmount, wgt % aqueous HPMC (10% solution) 42% triacetin 0.5%  water57.5%  

TABLE 4 Atom. Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C.RPM CFM PSI g/min 0 0 69 53.6 13 240 44.3 0 10 159 69 52.5 13 240 43.815.9 20 324 69 51.2 14 240 43.5 16.5 35 618 70 51 14 240 44.2 19.6

The final weight gain for the first layer (expressed as wgt %) was about2% based on the weight of the final tablet. The final weight gain forclear layer was 1.25%, based in the weight of the final tablet.

A microrelief was thermally transferred to the tablets using anapparatus 69 and transfer plate 76 described in FIGS. 21-24 at thepreferred values given in the specification, the thermoformedmicrorelief being applied as described in Example 1.

The coated tablets were stored for 3 weeks at 55° F. and 50% relativehumidity. After the three week period, the tablets still retained an80-90% diffraction efficiency. Tablets stored at over 100° F. faded.

In the above preferred examples the outer coating 12 comprised twocomplete coatings, both being applied using conventional rotating drum“pan” coaters for tablets. Colorants in the first coating produce adesired background color for the dosage form and provide contrast forthe holographic image or effect produced by the microrelief. It is alsopossible to add color to the core before compression. Often the particlesize of the aluminum lakes and titanium dioxide utilized in the firstcoating—if not fine enough—can interfere with the transfer process bysticking to the mold. This results in spotty, ineffective patterns.Thus, preferably, only the undercoat or the core carries a colorant; theovercoat is clear, and it is more stable.

A plasticizer in the overcoat has been found to be particularly helpfulin controlling cracking. In general, a plasticizer provides flexibilityto the layer 12. Plasticizers also provide a way to control theresponse, over time, of the layer 12 to air-borne moisture (humidity).Plasticizers such as propylene glycol, and sweeteners such as lactose,increase the effects of moisture on the layer 12 and the diffractionrelief it carries. By varying the amount and type of such hygroscopicmaterials, one can readily vary the hygroscopic nature of the coatingmaking it more likely to swell in humid weather. As noted above, overallhygroscopic swelling of the coating on the scale of the wavelength oflight will change the relief pattern sufficiently to be visible throughchanges in the effect produced by the diffraction relief. Control overthe response of the layer 12 to humidity can also determine the choiceand proportion of the thermoformable materials. Some suitable otherplasticizers which are hygroscopic include polyethyleneglycols.Plasticizers which have been found to be not as hygroscopic, includepolyhydrolic alcohols, glycerin, and triacetin.

HPC is more hygroscopic than HPMC, and the two can be mixed in variousproportions to vary in a corresponding manner the stability of thegrating structure in response to humidity.

Oils and waxes can be used similarly but to show the effects of heat,instead of moisture, on the layer 12 and the microrelief it carries.Some suitable waxes include mixtures of low melting point paraffin, andhigh melting point carnuba waxes which can be added during the pancoating process to affect the melting point of the diffraction grating.One skilled in the art can readily adjust the mixtures, and therebycontrol the fading of the holographic relief, over time, in response totemperature.

If the layer 12 is not coated onto a core or container (e.g., acapsule), it may be formed separately as a printed section or as alaminated section. Even without a separate adherent layer, materials inthe solution forming the layer 12 can be used to enhance the ability ofthe layer to adhere to a core, or to a capsule, or to another coating onthe core. When heated, HPMC will flow into and adhere to HPMC. The sameis true of HPC. The layer 12, when used as a fully-enclosing coating fora tablet, is in the approximate range of 0.25% to 7.5% of the totalweight of the dosage form.

The formulations identified above can be (1) formed into solid outerlayers or coatings around a core, (2) subsequently heated to soften(including liquefy) the layers, (3) molded to form a high resolutiondiffraction relief, and then (4) cooled to retain that relief pattern ina solid form when (5) released or de-molded. General characteristics ofthese materials are that they can be made to flow or bond at atemperature lower than that which will affect the core, can retain agrating with a phase displacement on the scale of the wave length oflight, are palatable, will not interfere with the release of the corescontents, and have a controllable heat and water stability in storage.

These materials are also capable of retaining a fine pattern, e.g., a½-1 micron spacing between raised portions, when exposed to thetemperature and humidity variations that are normally encountered inshipment, storage and use world-wide. Materials exhibiting thesequalities are termed herein “stable”. It is also significant that thematerials release from a mold easily, cleanly, and without damage to themicrorelief when they are cooled. They are also materials that have beenapproved by the responsible U.S. and international regulatory agency foruse in foods and pharmaceuticals.

Layers 12 formed of these materials are used to enclose the cores as inpan coating, or partially enclose a section of the core, as when theyare applied using known printing or lamination techniques. If the layersthemselves are formed into sections, the sections themselves can be usedas dosage forms after being made to absorb therein the contents of thepharmaceutically active agent, as described below in more detail withreference to FIG. 10.

FIG. 1 illustrates a tablet form of a dosage form 10 formed according tothe present invention carrying a coating 12 which fully covers a core14. This tablet core is typically one formed by standard powdercompression techniques. The layer 12 is preferably formed of thematerials described above, in particular, ones including as theirprincipal constituent a modified cellulose consisting of HPMC, HPC, orcombination thereof. A microrelief 16 capable of conveying informationwhen exposed to suitable radiant energy, typically a diffraction reliefexposed to sunlight and/or a conventional artificial light, is thermallyformed, by direct and indirect methods, using apparatus and techniquesdescribed below with respect to FIGS. 13-33. The microrelief is shown asbeing produced on both curved and flat faces 18 of the dosage form 10.The side surface 20 of the dosage form is generally straight (viewed invertical section or side elevation) and follows the overall outline ofthe dosage form when viewed from the top or bottom. This outline can, ofcourse, assume a wide variety of shapes such as circular, oval, diamond,rounded-corner arc diamond, polygonal, or many other shapes.

A particular feature of a preferred embodiment of the invention is thatthe faces 18 as shown in FIGS. 1-12 are characterized by 1) a shallow,convex curvature, generally along a circular arc as shown, or 2) a smallflat recess. In general it is more difficult to transfer onto and thenreconstruct a microrelief on a curved surface than a flat surface.Functionally, the degree of the curvature and the amount of the flatarea at the outer surface of the dosage form should be such so as toresist the twinning of tablets during the coating process and allow fora good diffraction relief to be created (the pattern of ridges andgrooves in the layer 12) and reconstructed (the viewed hologram). As afunctional test of the appropriate degree of twinning, preferablytwinning should be controlled to limit rejected twinned tablets to lessthan 0.5% of the total yield. As a functional test of the appropriatedegree of pattern reconstruction, preferably diffraction efficiencyshould be not less then 80%. Increase of pan-coating rotation speed(RPM), spray rate (g/min), run time, as well as inlet and exhausttemperature and air pressure in the coater, all affect the amount offlat area and/or degree of shallowness of curvature that can be usedbefore twinning affects limit yield. Preferred speeds rates andtemperatures are described in the above examples.

FIGS. 2-2C show an alternative curved-face dosage form (coated tablet)10 where both faces 18 are curved to resist twinning, but curved to anenhanced degree as compared with the shallow face curvature shown inFIG. 1. This tablet 10 is also fully covered with a thermoformable outerlayer 12. Both curved faces terminate at a straight side wall 20. Oneface of the FIG. 2 embodiment includes letters formed in one convexlycurved surface 18 of the dosage form. The lettering 22 is cut into theupper face 18 of the dosage form, as best seen in FIG. 2C, therebyreducing the face area subject to twinning. The microrelief can, forexample, produce a diffracted rainbow-like array of colors over thesurfaces 18 and around the lettering 22. On the upper surface thiseffect enhances and highlights the relief lettering 22, as well asproviding an aesthetically distinctive and attractive appearance.

FIGS. 3-3C disclose yet another embodiment of a tablet form of a dosageform 10 according to the present invention which is fully coated with alayer 12 and carries lettering 22. In this embodiment, the holographicpattern is applied only to a generally flat, central portion 18 a of theupper and lower faces 18, 18 (as shown) during the thermal forming.Again, the lettering 22 is preferably depressed from the upper surfaceto protect it and to surround it with a holographic effect. The uppersurface 18 a terminates in a surrounding shoulder portion 18 b that isinclined. In the embodiment shown it is generally flat in cross sectionand terminates in a “straight” side 20. The simultaneous provision of aflat central portion 18 a facilitates the replication of a microreliefin the layer 12 because the replication occurs on a flat surface.Depression of the lettering 22 also serves to assist in controllingtwinning. The microrelief 16 typically produces color, preferably arainbow-effect, which surrounds and highlights the lettering 22.

By way of illustration, but not of limitation, in the tablet form shownin FIGS. 3-3C, with a diamond plan configuration where the dosage form10 has a major axis length of about 0.55 inch and a minor axis width ofapproximately 0.40 inch, the shoulder 18 b extends laterallyapproximately 0.13 inch and has a height of approximately 0.02 inch. Thelettering 22 is cut downwardly into the face 18 approximately 0.008 inchand preferably has sloping side, as shown in FIG. 3C this slope ispreferably about 37.5°.

FIGS. 4-4C show another alternative embodiment of a tablet form of adosage form 10 according to the present invention that is fully coatedwith a layer 12 over a core 14. A principal difference between the FIG.4 and FIG. 3 embodiments is that the shoulder portions 18 b surroundingthe flat central portion 18 a are curved, preferably along a circulararc when viewed in vertical cross-section or side or end elevation. Theshoulders 18 b, 18 b have depth, for a dosage form 10 with theillustrative shape and size described above with respect to FIGS. 3-3C,of 0.06 inch. They each extend laterally for a distance of approximately0.10 inch. This amount of rounded shoulder embodiment has also proven tobe effective in controlling twinning despite having flat face portions18 a, 18 a. FIGS. 4-4C represents the currently preferred form for aholographicly enhanced dosage form 10 when a dosage form is formed as acompressed pharmaceutical or sugar core enclosed in a coated layer 12 ofa food grade thermally-formable material capable of receiving andretaining a fine resolution diffraction relief.

FIGS. 5-5C show another alternative embodiment of a tablet form of adosage form 10 according to the present invention which is fully coatedwith a layer 12. Like the FIGS. 4-4C embodiment, it utilizes flatcentral faces 18 a, 18 a, and rounded shoulders 18 b, 18 b, but theFIGS. 5-5C embodiment also has a central recess 24, 24 formed in each ofthe flat faces 18 a, 18 a. The recesses 24 each have a depthsubstantially equal to the height of the lettering 22 set into therecess. As with the other preceding embodiments, the configuration anddimensions can vary depending on factors such as the overall dosage formconfiguration and size, the nature and extent of the coating 12, and thepresence of the other twinning control mechanisms. The depth of therecess into which the microrelief is transferred also helps to protectit from abrasion. In a tablet with an overall arc diamond shape as shownin FIG. 5, and with the dosage form having a major axis length of about0.55 inch and a minor axis width of approximately 0.40 inch, the curvedshoulder extends over a depth of 0.028 inch and extends laterally forapproximately 0.07 inch with a curvature subtending on angle of about0.1 radian, and the central recess 24 has a depth of approximately0.0064 inch. The upper surface of the lettering 22 is generallyco-planar with the flat surface of the surrounding face portion 18 a. Asshown, only the upper recess 24 contains the lettering 22. Themicrorelief 16 is stamped into the generally flat and co-planar portionsof the lettering 22 and the surrounding regions of the flat face portion18 a.

FIGS. 6-6C show yet another embodiment for a dosage form 10 in the formof a tablet with a core 14 coated with a layer 12 and having roundedshoulders 18 b and a central recess 24 to control twinning, allaccording to the present invention. The FIGS. 6-6C embodiments differfrom the FIGS. 5-5C embodiment principally in that the lettering 22projects down rather then up in the central recess 26. FIG. 6C is adetailed sectional view taken along line C-C in FIG. 6 to illustrate theconfiguration of the recesses and the relative heights thereof. Amicrorelief 16 is typically formed in the layer 12 covering section 24.It may also be thermoformed in the surrounding bottom surface as well asthe flat surface 18 a surrounding both recesses 24 and 26. While thedouble recess dosage form configuration is more complex, it has theadvantage of providing a flat surface 26 to receive a diffraction relief16, while at the same time accenting the area around lettering 22. Forpurposes of illustration only, the dosage form shown in FIGS. 6-6C, withthe same general configuration and dimensions as the dosage forms shownin FIGS. 4 and 5, has a maximum depth in the first recess 24 ofapproximately 0.0054 inch, and a the maximum depth of the second recessof approximately 0.0064 inch. As before the depth of the recess intowhich the microrelief is transferred also helps to protect it fromabrasion. Again, these values are merely illustrative, and in no wayshould be construed as limiting the scope of this invention to thatparticular value, or even a near range of values.

FIG. 7 shows a tablet in which a section has been applied throughlamination. A compressed core 14 carrying a section 28 of layer 12,e.g., 1 to 2 microns thick, which has a high resolution diffractionrelief 16 formed on its outer surface. An adherent layer 30 bondssection 28 to the outer surface of the core. The thickness of layers 12and 30 are highly exaggerated in FIG. 7 for clarity. Suitable adherentsare water and/or alcohol-soluble and non-reactive with the materialsforming the core or the layer 12. They are preferably heat-activated andreliably secure the core to the section 28. A suitable adherent is waxor vegetable gum. In practice, it has been found however that theadherent will extrude or “squeeze out” along the edges of the sectionwhen it is affixed to the dosage form. To avoid this problem, thepresently preferred arrangement (shown in FIG. 7 as an alternativearrangement) of adhering section 28′ carrying a relief to a dosage formis to form the outer layer 12 of the dosage form and the section 28′ ofa material that will fuse to itself when heated. It is preferred to formthe section 28′ and to coat the dosage form core 14 or encapsulate thecore material 14 in the same material, HPMC. Alternatively, the sectionapplied does not have to have a preformed microrelief and so the degreeof heating used to form the relief will cause the materials of section28′ and this coating or capsule to flow into one another to adhere them.This allows a smaller amount of coating to be applied during panning andso further reduce twinning. HPMC will also form a shiny surface whenheat stamped which is attractive independent of a diffraction relief.

Section 28 can be applied in a continuous high-speed operation using alayer 12 in the form of a ribbon. The layer 12 is then advanced incoordination with a movement of cores 14 that place the adhesive coating30 of each section 28 in contact with an associated core 14. They areheated when the core and sections are in an opposed relationship and incontact with one another. The heating promotes the adherence of thesection to the core, and can also thermoform the microrelief pattern inthe layer 12 if this replication has not occurred earlier. The adheredsections are then cooled, and the section 28 is transferred. The ediblelayer 12 can be a combination of HPMC, HPC and modified starch. Anedible adhesive coating 30 (if a direct thermal bond is not utilized)can be a combination of waxes and vegetable gum plus triglycerides and asolvent. The transfer can be controlled and localized by using a stamperor thermal printer to transfer the section in a predetermined letter orshape by pressing against the dosage form.

As stated above, in order to address twinning issues on tablets withflat areas it is also possible to apply a section of outer coating layer12 by lamination or printing. When printing, layer 12 is applied in atraditional tablet marking machine. The layer can be applied as acontinuous section or in the form of ground solid particles of materialforming the layer 12, as described above. As well as printing sectionsof layer 12 onto the core, machines of this type can also be used toaugment layer 12 before and/or after the transfer of diffractive reliefsto accent areas and print letters to be used with the diffractiveimages. When printing complex images, each printed layer can be createdfrom a different composition of layer 12, as is described in other areasof this application, so to retain the images and effects produced by itsgrating at different temperatures and humidity conditions. Thus complexpatterns can be created which record the effects of maximum storageconditions over a range of environmental factors (i.e., ranges oftemperature and humidity). By way of example, two stripes (like sections28′ described above) of layer 12 can be applied, each of which changesits image at different relative humidities. The stripes can be printedonto the dosage form, one using a layer 12 formed using the materials ofExample 1 herein and the other using the materials described above withreference to Example 2.

FIG. 8 shows a hard capsule 10 that carries a core 14 within the capsuleas a powdery, granular or viscous mass. The capsule shell contains andprotects the core material, but in accordance with the presentinvention, it is also formed of a heat-formable layer 12 that can bethermal-formed with a microrelief pattern 16 directly into the inner orouter surface of the capsule. Suitable materials for the formation ofthe capsule include gelatin, starch, and HPMC, or mixtures therof.

FIG. 9 illustrates a soft gel capsule 10 according to the presentinvention which is similar in function to the hard capsule describedwith respect to FIG. 8, The hard and soft capsules are preferably formedof a gelatin material, preferably with a Bloom strength of 200 to 250,according to the present invention.

FIG. 10 shows a unit dosage form 10 according to the present inventionwhere the layers themselves are formed into sections, and are used asdosage forms themselves after being made to absorb or are formed with,the contents of the pharmaceutically active agent therein. Typicallylayer 12 absorbs the pharmaceutical in the manner of ink blottercarrying absorbed ink, or is formed with it from a common aqueoussolution. Absorption, e.g., by spraying the pharmaceutical into thepre-formed layer 12, is presently preferred. Preferred materials forthis section type dosage form are HPMC, gelatins, dextrins, andvegetable gums such as gum acacia, pollulan gum, and mixtures thereof.

FIG. 11 shows a temperature and humidity controlled container formultiple dosage forms 10. It contains sections for storage 29 and abacking layer 27 which can include a thermal and hygroscopic humiditybarrier to further control the moisture and temperature the dosage form10 is made to interact with.

FIGS. 12A-H each show, in top plan and side elevation, a tablet-typedosage form 10 that is coated with a outer layer 12 that carries amicrorelief 16. The tablets 10 each have an overall arcuate diamondshape in plan view and have two generally flat faces 18, 18. They differfrom one another in the mechanism used to reduce the area of the faces18, 18 to control twinning during the application of the coating layer12.

FIG. 12A illustrates a series of lateral grooves 19 formed in the core14 of the tablet. The area of the faces 18, 18 is reduced by the area ofthe grooves 19 at the faces 18, 18. The width of the grooves can bevaried especially for a given tablet configuration and coatingoperation. The reject rate due to the twinning is the test that measureswhether the groove is properly configured.

FIG. 12B shows the same tablet 10, but with a series of concentricgrooves 19′.

FIG. 12C shows a table 10 using a combination of the grooves 19 and 19′.

FIG. 12D shows a tablet 10 with a coating 12 with two central, generallyflat faces 18, 18 surrounded by an eight-sided, diamond-like array offlat-faced, inclined, shoulder portions 18 b′.

FIG. 12E shows a tablet 10 with a coating 12 carrying lettering 22 cutinto at least one face 18 together with a set of depressions 21 alsoformed in the otherwise generally flat faces 18, 18. Twinning is reducedin proportion to the combined surface area (at face 18) of the lettering22 and the depressions 21.

FIG. 12F shows a tablet 10 with a coating 12 that has raised, enlargedportions 23, 23 at both ends of the tablet. The end portions 23, 23control twinning by physically interfering with a face 18 to face 18contact between tablets 10.

FIG. 12G is a variant on the FIG. 12F embodiment when the raised endportion 23′ smoothly merges with the body of the tablet at both ends toreinforce the portions 23′, 23′.

FIG. 12H shows another embodiment of the tablet 10 with generally flatfaces 18, 18 and a central, generally hemispherical, projection 27generally centered on each face 18. The projection 27 can, of course,take a variety of shapes and can be used in plural form on each face.

Turning now to apparatus and techniques and modes of processing suitablefor producing the dosage forms 10, FIGS. 13-15 illustrate an apparatus30 which uses a semi-elastic mold, or “transfer plate” 32 configured asa belt and adapted to move in coordination with an array of the dosageforms 10 each carried in suitable aligned depressions 33 on a conveyorbelt 34.

As shown, the dosage forms 10, have been coated, at least in part, witha layer 12 and are arrayed across the conveying belt 34 in a series ofmutually-spaced lines. A like pattern of the depressions 33 eachreceives one of the tablet or capsule types of the dosage forms 10 toestablish this array. One of the rolls 36 a, 36 b that carry the belt 34is driven to advance the dosage forms, right to left as shown, to afirst relief replicating assembly 38 having a frame 38 a, and threerolls 38 b, 38 c and 38 d journalled in the frame. The rolls carry thecontinuous belt transfer plate 32. At least one of these rolls is alsodriven to move the transfer plate in coordination with movement of thebelt 34.

The transfer plate 32 is preferably formed as a thin, temperatureresistant sheet of a material that can retain a high resolutionmicrorelief such as a diffraction pattern on its outer surface, which ispreferably thermally conductive and able to flex sufficiently totransfer the relief to a heat-softened and/or liquefied layer 12 on oneface 18 (FIGS. 1-12H) of dosage form 10 while accommodating to itsshape. The preferred material is a diffractive surface composed of anelectoformed metal or a heat resistant plastic, both with a thickness inthe range of 1 to 5 mils. The tension in the transfer plate 32 producesa downward pressure urging the microrelief pattern on the transfer plateto be replicated in the layer 12 on the dosage forms as they passthrough a nip defined by the belt 34 (at the roll 36 a) and the opposedportion of the transfer plate 32.

The coating 12 is heated, preferably just before and/or during thisreplication, to a degree that softens it sufficiently to receive themicrorelief. A typical temperature of the layer 12 produced by thisheating is in the range of 90° C. to 150° C., and preferably about 125°C. It can be effected by heating the transfer plate, the dosage formcoating 12, or both. The heat source can be a stream of hot air, anelectric resistance heater, a pulse of a laser, a source of infra-redradiant energy, a fluid-heated cylinder, or any of a wide variety ofknown devices. In the apparatus shown, preferably the roll 38 b isheated, and it in turn heats the transfer plate. If the dosage form isheated, it can be heated as a whole, or heated with a controlled burstof radiant energy (e.g., laser light) that heats only the outer layer12, but does not significantly increase the temperature of the core 14.The transfer of the relief can occur in a fraction of a second, with 0.3to 3 second being typical, and with a pressure of between 5 and 10 kgper pill. After transferring the microrelief to the layer 12, the layeris rapidly cooled to set the microrelief in the layer. Where release isa significant concern, a sliding mechanism is employed to shift the beltthat holds the dosage form array to the side effecting the release.Again, a wide variety of cooling techniques can be used such as jets ofchilled air, cold rolls, ambient air and radiant cooling, or the actionof the cool core 14 (FIGS. 1-12H) as a heat sink. In the apparatusshown, preferably roll 38 d and 36 a are cooled, which cools thetransfer plate 32, and the dosage forms carried on the belt 34. Thecooling also aids the release of the outer layer 12 from the transferplate.

The belt 34 and transfer plate 32 move in coordination until the coolinghas set the microrelief. A guide member 40 retains the dosage forms inthe belt 34 as it rotates around a cushioned roll 36 a to allow forvariations in dosage form thickness and to invert the dosage forms 10just embossed. While a continuous belt is shown, other conveyancearrangements can be used, e.g., a chain drive carrying a series ofmutually spaced, slat-like segments 35 (FIGS. 20 and 20A) that carry thedosage forms and transfer plate. Each slat segment 35 can then be joggedalong its length independently of the movement of the other segments tofacilitate the release of the dosage forms from the transfer plate. Theslates are preferably mounted on bolts or pins 37 captured in elongatedopenings 35a that guide the jogging movements. Springs 39 hold the slatsin a normal position. A fixed cam plate 41 at the side of the belt 34engages the slats as they travel and produces the jogging movement inopposition to the spring force.

The dosage forms 10 transfer to an array of depressions 33′ in belt 34′.It carries them to a second print assembly 38′ that transfers adiffraction microrelief on the opposite face of each dosage form 10. Theassembly 38′ has the same construction as the assembly 38. Themicrorelief pattern, of course, may differ. The presenting coated dosageform face or surfaces are heated, the microrelief pattern thermallytransferred, cooled, and released, as with the assembly 38, as they arecontinuously carried through the assembly 38′. Upon leaving the assembly38′, the dosage forms 10 travel in belt 34′ and fall onto a take-awayconveyor 44.

FIGS. 16 and 17 show an alternative apparatus 45 according to thepresent invention which, like the apparatus 30 of FIGS. 13-15, uses twotransfer plates 46, 46′ to replicate a high resolution diffractionrelief on opposite faces 18 of dosage forms 10 carried in opening 48 ofmoving conveyor belt 50. The upper rim of belts 50 moves right to left,as shown, as dosage forms 10 are fed into the openings 48 which alignsand transports the dosage forms. The openings 48 extend through the belt50. A panel 52—or a belt or other equivalent member—supports the dosageforms at their bottom to retain them in the openings 48 before and afterthe transfer plates 46, 46. The transfer plates 46, 46 are eachjournalled on rolls 54 a, 54 b that drive the transfer plates incoordination with the movement of the belt 50. The transfer platessandwich the dosage forms there between. Rolls 55 disposed behind eachtransfer plate adjacent the dosage forms are heated to heat the dosageforms through the transfer plates to a suitable temperature, again,preferably 90° C. to 150° C. Cooling rollers 56 then help in demolding.Note that the thinness of the transfer plates not only facilitates rapidheat transfer, but also facilitates the application of a generallyuniform pressure over the dosage form surface receiving the microrelief,despite the fact that the surface might not be flat, e.g., the curvedsurfaces 18 of the dosage forms 10 shown in FIGS. 1-2. A uniformdistribution of the pressure can be promoted by using a resilientpressure member, e.g., a foam sleeve on alternating rolls 54 and 54′,and 56 and 56′ below the dosage form such that each heating or coolingroller is pressing the bottom or top of the dosage form against anopposing resilient pressure member.

The transfer plates 46 and 46′ can be pre-curved at the point of contactwith the dosage forms to facilitate the transfer on to irregularlyshaped sections. The microrelief pattern on the transfer plate can alsobe optically predistorted to accommodate for the reconstitution of animage on dosage forms with curved irregularly shaped sections. Thedosage forms are thus simultaneously and continuously replicated with amicrorelief pattern on both sides of complexly shaped surfaces and arecarried around roll 58 a and held in the holes 48 by a conforming guidemember 40a. As the dosage forms clear the guide, they fall onto a takeaway conveyor 44 a.

FIGS. 18-19 show a twin moving belt-like transfer plate apparatus 59according to the present invention, which is an alternative embodimentemploying features of the FIGS. 13-15 and FIGS. 16-17 apparatus 30 and45 but which avoids the dosage form transfer between belts attendant theFIGS. 13-15 embodiments. An array of dosage forms 10 with coatings 12 onat least some portions of their upper and lower faces are transported inopenings 61 formed in a continuous belt 60. The openings 61 extendthrough the belt 60, which acts both as a transport and an alignmentgrid. Its upper run travels right to left, as shown in FIG. 18, over afirst roll 62 and then between a replicating assembly 38 and a backingroll 64. The first roll 38 a of the assembly 38 heats the transfer plate32 containing the microrelief pattern to be transferred, here adiffraction relief with a holographic image, which then is pressed intoa layer 12 to replicate the structure. The belt tension and nipdimensions set the pressure. Preferably the backer roll and/or thetransfer plate have a resilient layer that distributes the applied forcegenerally uniformly, and urges the thin transfer plate into the layer 12even if it is in recessed or curved portion of the dosage form. Roll 38b of the assembly 38 is cooled to set the microrelief. De-molding is aswith the previously discussed embodiments.

Continued transport then carries the dosage forms through a mirror-imageprint assembly 38′ and cooperating backing roll 64 that replicates arelief on the opposite face of the dosage forms 10. A guide 66 carriesthe dosage forms around to a take-away conveyor 68.

FIGS. 21-24 show another apparatus 69 according to the present inventionfor transferring a microrelief pattern into the coating 12 of a dosageform 10. This embodiment uses a pallet assembly 71 that has arectangular frame 70 that supports a registration plate, or grid, 72that in turn holds an array of the dosage forms 10 in openings 74 thatextend through the grid. A thin, rectangular transfer plate 76,preferably formed of metal, and having a microrelief pattern etched orotherwise formed on one face is placed in the frame. The transfer plate76 is registered on pins or surfaces (e.g., the interior surfaces of thesidewalls of the frame 70) if it is desired to have precise registrationbetween the relief pattern and the dosage forms. An elastic base 77 alsoheld in the frame 70 supports the dosage forms from the bottom. It canhave depressions aligned with the openings to accommodate curved orthick dosage forms and to protect the supported surface from mechanicalabrasion. The apparatus carries the pallet 71 along a generally linearprocessing path that includes intermittent stops at a series ofstations.

The frames are carried on a continuous conveyor belt, as best seen inFIG. 23, in two stages that each transfer a microrelief pattern 16 ontoone face 18 of each dosage form 10. At a second station 82, apick-and-place mechanism 84 transfers plate 76 on a parallel transferplate-return conveyor 86 and move it onto a frame 70, over an array ofthe dosage forms 10 loaded into the grid 72. At station 88 athermal-pressure element 90 lowers onto the transfer plate, heats atleast the portions of the coatings 12 adjacent the transfer plate to thedesired temperature (90° C.-150° C., and preferably about 125° C.), andpresses the transfer plate into the heated coating 12 to replicate themicrorelief pattern. This typically requires about ½ second, but canfall in the range of 0.3 to 3.0 second. The thermal transfer element, asseen in FIG. 21, preferably has a heated pressure plate 91 that isgenerally co-extensive with the transfer plate to heat it and applypressure to it uniformly. As noted above, a resilient layer, here thefoam rubber base 77, helps to promote an even distribution of theapplied force. A typical pressure is 5 kg to 30 kg/per pill with about10 kg/per pill being preferred. After imprinting, the heat transferelement 90 moves and lifts from the transfer plate and the pallet 71moves through several air cooling stations 92 (e.g., regions undercooled air outlets 93) which set the microrelief. At station 94, thetransfer plate is then lifted from the pallet 71 to de-mold it from thedosage forms 10, and transfer it to the conveyor 86 for recirculationback to station 82.

A turnover mechanism 98 flips the dosage form array sandwiched betweenthe two frame assemblies through 180° onto a second linear conveyor 100of the second stage. This second stage repeats the microreliefreplication process of stage one to place a microrelief on the oppositeface 18 each dosage form 10. After the transfer plate 32 is removed atstation 94, the registration grid and frame are carried around roll 102to discharge the dosage forms to a take-away conveyor 104 feeding acollection bin 106.

FIG. 25 shows a rotary apparatus 108 for thermoforming a high resolutiondiffraction relief onto a layer 12 on an array of dosage forms 10carried in a pallet 71. A diffraction pattern transfer plate 76 isplaced on each incoming pallet 71 at 110. The pallet is then transportedto a position 112 where it is gripped between a pair of members 114, 116each supported on the end of an arm 118 rotated by a hub 120. At leastone arm 118 of each pair of pivots to open, close, and press thetransfer plate towards the dosage forms. As the hub rotates, a grippedassembly is heated and pressed at angular position 119, cooled atposition 120, and released by opening the members 114, 116 at position122 where the assembly is transported to a de-molding and transfer plateremoval station 124.

FIGS. 26 and 27 show a rotary apparatus 126 according to the presentinvention that receives an intake of dosage forms 10 that are fedvertically into a registration frame 128. An associated shuttleapparatus 130 moves both upper microstructure (relief) transfer element(“MTE”) 132 and lower MTE plate 134 into and out of positions alignedwith the frame 128. At the intake position 126, the upper MTE 132 is“open”, that is, shuttled to the side, while the lower MTE 134 is“closed”, that is, in position under the frame 128 to support the dosageform 10 in opening 136 in the MTE 128. The upper MTE then closes—as theapparatus rotates the dosage form(s) and MTE's through thermoforming andcooling positions 138 and 140, respectively. At position 142, the lowerMTE 134 shuttles to an open position to allow the dosage forms to fallout of the frame 128 onto a chute, belt or other off-take arrangement.

It will be understood that the shuttle mechanism can include cam actionor other equivalent mechanical arrangement to develop force that pressesthe MTE's toward the heated dosage form layers 12, and/or facilitatesthe release of the dosage forms from the MTE's. Also, pressing canutilize a separate pressure and/or heat applying member operating in themanner of the thermal transfer element 90.

FIGS. 29 and 30 show another apparatus 138 according to the presentinvention that rotates a set of tablet punch dies 140 each having a body142 with a central bore that defines the outline of this dosage form andupper and lower punches 144, 146 mounted for a coordinated,reciprocating, co-axial movement in opposite ends of the body 142. Thepunch dies are generally of standard design for the manufacture ofcompressed powder tablets, except that (1) the end face of each punch144, 146 can carry a replaceable die with a high resolution microreliefpattern formed therein, and (2) a crescent-shaped tab 148 is mounted ina slot 150 in the side of the body 142 to execute a pivotal movementbetween the dosage form-in-die position 148 a, shown at the left-mostdie in FIG. 30, and the dosage form-ejected-from-die position 148 b,shown in the right-most die in FIG. 30. Alternatively, a small, movableclamp (not shown) can grip and move the dosage into, and hold them inposition in, the dies 14, and then remove them from the dies 14.

In the apparatus 138 the dosage form 10 itself, not the punch or thedie, is heated to soften the layer 12 before it is introduced to theapparatus 138. The heated dosage form is then fed into the die throughthe slot 150 with the tab in position 148 b. Movement of the dosage formfully into the die is effected by rotating the tab 148 to position 148a. The apparatus then rotates to index the die, with the hot dosage formloaded therein, to a position where the cold punches 144, 146 are drivenaxially to transfer the microrelief pattern to the layer 12. Because thepunches are relatively cold and have a large mass as compared to theheated dosage form, they quickly cool the layer 12. The punches are thenwithdrawn to de-mold the microrelief thus formed. Further step-wiserotation of the apparatus 138 brings the coated dosage form 10 with themicrorelief(s) 16 to a discharge position. Operation of the tab 148 tothe position 148 b ejects the dosage form 10 from the die. The die punchis then ready to receive another heated dosage form. Alternatively, ofcourse, the punches 144, 146 can be heated, and the dosage formsintroduced at room temperature.

FIG. 31 is a flow diagram showing the thermoforming manufacturingprocess of the present invention in its most general form. At block 152a layer 12 is solid state is provided, whether as a full or partialcovering of a core 14, a hard or soft capsule shell, a label to beaffixed to a core or capsule, or itself as a carrier of a pharmaceuticaldispersed therein. At block 154 the layer is heated, whether by a moldor die or directly, to a degree sufficient to receive the microrelief.At block 156, the microrelief pattern is transferred into the heatedlayer. At block 158, the microrelief thus formed in the layer 12 iscooled to set the microrelief sufficiently that it does not degrade whende-molded. At block 160 the layer 12 is released from the mold (transferplate, MTE, etc.).

FIG. 32 shows an alternative arrangement for the formation of aholographic microrelief pattern directly into an outer layer 12 on adosage form 10. A high energy laser light source 161 (shown as twosources 161, but typically it is one source whose output beam is split)produces two beams 162, 162 of laser light that interfere in a region164 to produce a desired interference pattern 16 of light intensitymaxima and minima. A dosage form is positioned with its layer 12 in theregion 164. Lines of maximum light energy creates corresponding grooves(a microrelief) into the layer 12. Lines of minimum light intensityproduce corresponding ridges in the layer 12. A microrelief pattern isthus formed directly by a pattern of light energy “burned into” thelayer 12. Note that because the interference pattern occurs over aregion, it automatically adjusts to variations of the layer 12 from aperfectly flat condition.

FIG. 33 shows a further alternative apparatus 170 according to thepresent invention that transfers a high resolution microrelief into theouter coating 12 of dosage forms 10, particularly tablets. Thisembodiment is similar in its construction and mode of operation to knownhigh speed printing apparatuses. The dosage forms 10 are fed to anintake hopper 172. A feeding apparatus 174 takes the dosage forms fromthe hopper 172, orients and aligns them, and presents them for transferto a first conveyor wheel 176. An array of depressions in the outerlayer of the wheel 176, or other known arrangements, carry an array ofthe dosage forms on the outer periphery of the wheel 176. A guard rail178 holds the dosage forms 10 in place on the conveyor 176 as it rotatesthem from the feeder 174 to a second conveyor wheel 180. The rotation ofthe conveyors 176 and 180 are coordinated so that the dosage formstransfer from the outer surface of the conveyor 176 to that of theconveyor 180 at the nip 182.

The conveyor wheel 180 then rotates the dosage forms to a nip 184 wherea heated cylinder 186 that carries a microrelief transfer plate 32′ onits outer surface. A microrelief pattern, preferably a high resolutiondiffraction relief, is electroformed or otherwise created using knowntechniques on the outer surface of the plate 32′ and positioned tocontact the layers 12 on a first face of the dosage forms 10 as theypass through the nip 184. The heat of the cylinder 186 softens the layer12 to replicate the microrelief pattern in it. The size of the nipspacing, in conjunction with particular dosage forms, transfer platesand carrier wheel constructions (e.g., with or without a resilientbacking layer under the dosage forms like layer 77 in the FIGS. 21-24embodiment) produces the desired degree of pressure to affect thereplication for a given layer 12 and a given degree of heating. Also,with the foregoing embodiments, a pressure in the range of 5 to 15kg/pill, and preferably about 10 kg/pill, is preferred. A guard rail(not shown) like rail 176 may be used over the run to the nip 184, andin conjunction with other conveyor wheels runs, e.g.,to hold the dosageforms on the wheel 180 after they leave the nip 184 and continue to nip188 where the dosage forms again transfer to conveyor wheel 190.

Conveyor wheel 190, constructed like conveyor wheels 176 and 180,receives the array of dosage forms each having a microrelief in theirouter layer 12 and carries them to a second heated cylinder 192 thatrotates in registration with the wheel 190 to replicate a microrelief ona second face of the dosage forms in the manner described above withrespect to heated cylinder 186 at nip 194. After replication of themicrorelief at the nips 184 and 194, the layer 12 is cooled in any ofthe ways discussed above to retain the microrelief in the layer 12 andfacilitate a demolding from the transfer plates 32′, 32′.

Having been embossed with a microrelief 16 on two opposite faces, thedosage forms 10 leaving the nip 194 are carried on the conveyor wheel190 to an output chute 196 where the demolder dosage forms fall off thewheel 190 assisted by the force of gravity and slide down the chute 196.

There has been described a dosage form that can selectively retain andreconstruct optical information and effects while being compatible withmodern high-speed production techniques. The dosage form can take avariety of configurations, including a coated tablet, a capsule, and Ifthe layers themselves are formed into sections, they can be used asdosage forms after being made to absorb the contents of thepharmaceutically active agent of the core therein. The holographicimages or effects can provide brand identification, controlcounterfeiting, and provide quality control. The dosage forms can bemade using materials that have regulatory approval for foods orpharmaceutical uses.

There has also been described a variety of machines and processes forthe production of these dosage forms. These machines and processes arecompatible with modern production speeds and techniques. In themanufacture of dosage unit forms such as tablets, they also resisttwinning.

While this invention has been described with respect to its presentlypreferred embodiments, other modifications and variations will occur tothose skilled in this art. For example, those skilled in the art willreadily understand that the products, apparatus, and manufacturingprocesses described herein can also be adapted to the production ofnon-pharmaceutical cores such as placebos and include cores made ofmaterials such as sugar, gum, hard jellies, or a variety of confections.Such modifications and variations are intended to fall within the scopeof the appended claims.

1-28. (canceled)
 29. A method of producing a microrelief on aningestible dosage form having a core which can contain apharmaceutically active substance and a pharmaceutically acceptablecarrier, comprising the steps of: a. coating said core with a layer of athermo-formable material that can receive and retain a holographicdiffraction pattern; b. providing a plate having a holographicdiffraction pattern formed on at least a portion of a first surfacethereof; c. heating at least one of said plate and said coating duringor prior to the time when they are in said opposed relationship; d.pressing said first surface into said coating to replicate saidholographic diffraction pattern in said coating; e. cooling said coatingthus replicated; and f. demolding said first plate surface from saidcoating.
 30. The holographic dosage form production method of claim 29wherein said coating is pan coating and further comprising the step ofcontrolling twinning of said coated tablets.
 31. The holographic dosageform production method of claim 30 wherein said twinning controlcomprises forming said core with at least one curved face that receivessaid coating and said pressing.
 32. The holographic dosage formproduction method of claim 31 wherein said curvature is sufficient toresist twinning, but not sufficient to distort the holographic imagepressed into in said coating.
 33. The holographic dosage form productionmethod of claim 32 wherein said core face is generally circular and,measured as an angle in a plane through the face, the curvature is inthe range of about 0.6 radian to about 0.9 radian.
 34. The holographicdosage form production method of claim 30 wherever said twinning controlcomprises forming said core with a recess within at least one face ofsaid coat, said recess having a generally flat bottom that receives saidcoating layer.
 35. The holographic dosage form production method ofclaim 34 wherein said recess is sufficiently shallow that said pressingtransfers said holographic pattern reliably.
 36. The holographic dosageform production method of claim 42 wherein said recess is less thanabout 0.01 mm.
 37. The diffractive dosage form production method ofclaim 29 wherein said coating includes said thermo-formable materialbonding reliably with said core.
 38. The holographic dosage formproduction method of claim 29 or 37 wherein said thermo-formablematerial selected from the group consisting of: gelatin,hydroxypropylmethylcellulose (HPMC), hydroxyproplycellulose (HPC),modified food starches, waxes, vegetable gums and combinations thereof.39. The holographic dosage form production methods of claim 38 whereinsaid material includes solids of a modified cellulose, a plasticizer,and a colorant.
 40. The holographic dosage form production method ofclaim 38 wherein said coating produces a layer in the range of 0.25% to7.25% of the weight of said dosage form.
 41. The holographic dosage formproduction method of claim 29 further comprising transporting saidcoated cores to a position opposite said first surface, and wherein saidplate providing comprises continuously advancing a belt of asemi-flexible material containing said pattern on at least one surfacethereof in coordinating with said transporting of said coated dosageforms.
 42. The holographic dosage form production method of claim 41wherein said semi-flexible material is selected from the groupconsisting of: a thin sheet metal, rubber, a laminate of thin sheetmetal and a layer of a resilient backing material opposite said firstsurface, and a rubber and metal composite.
 43. The holographic dosageform production method of claim 42 wherein said thin sheet metal is anickel composite with a thickness of 1 mils to 5 mils, and saidholographic diffraction pattern is electroformed on said first surface.44. The holographic dosage form production method of claim 41 whereinsaid transporting also aligns said coated cores.
 45. The holographicdosage form production method of claims 41 or 43 wherein said coatedcore facing said plate during said pressing is non-planar, and said beltflexibility is sufficient to allow said belt to conform to saidnon-planar coating desiring said pressing.
 46. The holographic dosageform production method of claim 41 wherein said transporting comprisesconveying of a linear array of said coated cores in a parallel, closelyspaced relationship with a portion of said belt, and moving said belt incoordination with said conveying.
 47. The holographic dosage formproduction method of claim 46 wherein said heating is a rapid, localizedheating of said belt during said pressing.
 48. The holographic dosageform production method of claim 47 wherein said heating raises thetemperature of said diffraction pattern on said belt to a temperature inthe range of 90-150 C.
 49. The holographic dosage form production methodof claim 47 wherein said pressing comprises a brief deflection of saidheated belt that places said diffraction pattern in said coating tocreate said replication of said diffraction pattern in said coating. 50.The holographic dosage form production method of claims 29 and 47wherein said pressing occurs for about 0.3 to 3.0 second.
 51. Theholographic dosage form production method of claim 46 wherein saidcooling is a rapid, localized cooling that begins immediately after saidpressing has formed said diffraction pattern in said coating.
 52. Theholographic dosage form production method of claim 51 wherein saiddemolding comprises a resumption of said mutually spaced relationshipbetween said coating as said coated and said belt as they continue tomove in coordination, after said cooling has begun. 53-62. (canceled)63. A method of producing a microrelief on an ingestible dosage formwhich can contain a pharmaceutically active substance and apharmaceutically acceptable carrier, comprising the steps of: a.providing a layer of material forming at least a part of the dosage formhaving a first surface, said material being thermoformable to receive,and once formed, retain, a holographic diffraction pattern on said firstsurface; b. providing a holographic diffraction pattern; c. replicatingsaid holographic diffraction pattern to said first surface bythermoforming said pattern onto said first surface; and d. rapidlycooling said thermoformed holographic diffraction pattern thusreplicated.
 64. The method of claim 63, wherein providing a holographicdiffraction pattern comprises producing an interference pattern usinglaser light.
 65. The method of claim 64, wherein said laser light isconstituted by two laser light beams split from a single laser lightsource.
 66. The method of claim 63, wherein said active substance andcarrier are contained in a core and said layer overlies said core.
 67. Amethod of producing an optical pattern on a surface of an ediblearticle, where the optical pattern interacts with incident light toproduce a visible image or effect, comprising the steps of:
 67. A methodof producing an optical pattern on a surface of an edible article, wherethe optical pattern interacts with incident light to produce a visibleimage or effect, comprising the steps of: providing a laser; causingsaid laser to emit first and second beams of light; and causing saidfirst and second beams of light to interfere to produce an interferencepattern on the surface of the edible article, and wherein theinterference pattern produces the optical pattern on the surface of theedible article.
 68. The method of claim 67, wherein said interferencepattern is comprised of light intensity maxima and minima.
 69. Themethod of claim 67, wherein the optical pattern is comprised of aplurality of grooves produced by lines of maximum light intensity insaid interference pattern, and a plurality of ridges produced by linesof minimum light intensity in said interference pattern.
 70. The methodof claim 68, wherein the optical pattern is a microrelief.